PROJECT SUMMARY (SONG, JI) Having reliable tools for selective, simultaneous in vivo determination of multiple neurotransmitters in real-time will allow for unprecedented acquisition of information key to understanding the underlying mechanisms and neurological pathways of numerous brain-associated mental disorders and diseases, such as Parkinson?s and Alzheimer?s diseases. In these examples, there is a malfunction or a degeneration in the neural signaling pathways that involve releasing and absorbing of various neurotransmitters which, if fully uncovered, can help better understand the cause of such neural disorders and potentially help the development of treatments and cure. As such, there is a great need for establishing an implantable sensor technique to quantify numerous neurotransmitters in parallel, rapidly, and selectively for extended periods of time in a living brain, without causing neuro-inflammation. Our long-term goal is to develop an integrated implantable and biocompatible device that provides accurate and fast determination of multiple neurotransmitters and that reduces inflammation at the implanted area to preserve the longevity of the device performance. Our goal will be achieved by pursuing the following two Specific Aims: (1) Implementation of a microscale sensor array for multi-species neurotransmitter detection, and (2) Development of a flexible and biocompatible device with microfluidic anti-inflammatory drug delivery system. Aim #1 will be achieved by utilizing molecularly imprinted polymers to selectively recognize the target analyte for the identification and quantification of the major mammalian neurotransmitters. A multi-analyte sensor array will be constructed by forming each individual sensing element with a unique molecularly imprinted polymer patterned on a microfabricated electrode. The functionality of the multi-analyte sensor array will be demonstrated by implanting the device at the ventral tegmental area (VTA) of a live rat brain as a model to observe the dynamics of neurotransmitters in VTA. Six target neurotransmitters are selected as analyte: dopamine, serotonin, norepinephrine, histamine, gamma- aminobutyric acid and acetylcholine. Once the sensor is securely positioned in the VTA, a neural stimulant is administered to observe the changes in the level of neurotransmitters that occurs in the VTA. Aim #2 will be achieved through the use of flexible and biocompatible materials, in conjunction with a microfluidic anti- inflammatory drug delivery system to minimize the foreign-body immune response and thus enabling long-term in vivo monitoring capability. The effectiveness of the histamine H4 receptor antagonist drug and the pro- inflammatory cytokine inhibitor drug will be studied by administering them through the microfluidic injection system directly into the implanted site and observing the expression of immune responses.